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A recent article by Pasceri et al1 suggested a significantly higher prevalence of Helicobacter pylori infections in patients with ischemic heart disease compared with matched controls. Two editorials in the same issue of Circulation critically evaluated existing knowledge regarding the association between chronic inflammation and atherosclerosis2 and the potential use of antibiotic therapy.3 Although there appears to be increasing evidence that low-grade inflammation induced by prior exposure to infective agents such as Chlamydia pneumoniae, cytomegalovirus, or H pylori might play a role in the development of atherosclerotic lesions, there is controversy regarding a proven pharmacological rationale for antibiotic therapy for atherosclerotic vascular disease. Pasceri et al1 conclude that eradication of H pylori may play a future role in the prevention of ischemic heart disease.

In our opinion, macrolide antibiotics have many properties that should be considered in the design and evaluation of clinical trials in ischemic heart disease. First, macrolides appear to exert potent anti-inflammatory effects. In the lung, erythromycin seems to ameliorate neutrophil-induced endothelial cell injury by affecting not only neutrophil functions but also the release of nitric oxide from endothelial cells through the action of cAMP-dependent protein kinase.4 Erythromycin has also been reported to modulate bleomycin-induced pulmonary fibrosis, possibly through suppression of tumor necrosis factor-α (TNF-α) and platelet-derived growth factor (PDGF), while reducing accumulation of inflammatory cells in the lung.5 In the treatment of chronic sinusitis, macrolides may affect interactions between antigen-presenting cells such as macrophages and CD4-positive T lymphocytes.6 Treatment of human pulmonary artery endothelial cells with erythromycin also appears to attenuate endothelial cell injury induced by activated neutrophiles, partially via inhibition of free radicals/superoxide.7

These potent anti-inflammatory effects might contribute to a beneficial effect of macrolide therapy in ischemic heart disease8910 independently of a complete eradication of infective organisms from atherosclerotic lesions. In the ROXIS pilot study,9 patients with unstable angina or non–Q-wave myocardial infarction were randomized to treatment with roxithromycin independently of C pneumoniae IgG baseline titers. A significant reduction in primary clinical end points was seen after 1 month in the roxithromycin group. The authors suggested that anti-inflammatory action of roxithromycin may have contributed to plaque stabilization. Future trials should not neglect the anti-inflammatory actions of macrolides as urgently needed scientific studies are initiated.

Response

We appreciate the comment of Zellner and Chou about the possible therapeutic implications of our study. Several recent studies have shown an association between ischemic heart disease and various chronic infections, including Chlamydia pneumoniae, cytomegalovirus, and Helicobacter pylori.R1 Although these evidences come merely from case-control studies and may be also due to several confounding factors, we found that the association between H pylori infection and ischemic heart disease was due only to a more virulent strain of Helicobacter, thus supporting the hypothesis that the association is secondary to the chronic inflammatory response induced by this strain.R2 Whether appropriate drug treatment against these agents may be effective in primary or secondary prevention of ischemic heart disease is still unknown. Two recent small, secondary prevention trials have suggested a beneficial effect of short-term macrolide antibiotic treatment (designed as an anti-Chlamydia treatment) in patients with ischemic heart disease.R3R4

As outlined by Zellner and Chou, macrolides, in particular roxithromycin, also have important immunomodulatory effects.R5 Because there is consistent evidence that inflammation plays an important role both in acute coronary syndromes and in the chronic evolution of atherosclerosis, the immunomodulatory effects of macrolides should be taken into account in interpreting the results of clinical trials. Yet, although long-term treatment with macrolides has been associated consistently with immunosuppression, short-term treatment, such as that used in one of the trials,R3 may actually enhance immunologic and inflammatory responses in ex vivo experiments.R5 Furthermore, it is difficult to distinguish between the anti-inflammatory and antibacterial effects of macrolides because there is no strong relationship between serum antibodies and the actual presence of C pneumoniae. Conversely, the presence of specific serum antibodies is usually associated with gastric infection by H pylori. Because the incidence of new infection after eradication is negligible, a simple 1- to 2-week treatment might yield effects even after many years, and subjects might be chosen according to the presence of the germ. Thus, studies on eradication of H pylori could easily distinguish the antibacterial effect from other possible effects of the treatment (anti-inflammatory but also antioxidant or antithrombotic).

It is worth noting that we did not find any specific association between H pylori infection and acute coronary syndromes or severity and number of coronary lesions.R2 Because H pylori infection is long lasting (often lifelong) and is usually acquired during childhood, it might have a more important role in the early stages of atherosclerosis than in its late complications. Finally, H pylori infection (as well as Chlamydia or cytomegalovirus infections) is quite prevalent among individuals without ischemic heart disease and absent in many of those with ischemic heart disease. Therefore, it appears essential to establish the specific mechanisms that confer individual vulnerability or protection toward ischemic heart disease before large clinical trials are required.